Abstract Individual variations in immune status and function shape responses to infection and contribute to disease severity and outcome. Infections with West Nile virus can be asymptomatic or severe, even leading to death, and no effective therapies or vaccines are available. Thus, identifying molecular signatures of immunity and phenotypes of susceptibility is essential to guide development of improved diagnostics, therapeutic interventions and future vaccines. We propose studies with a coordinated Systems approach for investigation of stratified subjects with West Nile viral infections to define how components of the immune response contribute to divergent outcomes. We will employ recent advances in high-throughput and high-resolution technology to profile individual immune responses in order to identify the molecular signatures defining divergent responses to West Nile virus infections. We will use shared platforms such as CyTOF, metabolomics, and innovative nanowell cytometry linked to single cell RNA-seq to provide insight into the immune responses to WNV. Our coordinated in-depth systems analysis includes for the first time the phenotype and functionality of neutrophils, platelets, and metabolomics in divergent clinical outcomes. Through integrating multiple immune components, we will define response profiles that correlate with successful outcome of infection. Strengths of our proposal are the well characterized clinical populations, the coordinated in-depth interrogation of multiple cell types and responses, the experienced and coordinated research team, the interrogation and integration of multiple variables that influence immune responses, and established HIPC consortium networks.